阅读说明：本技术 苯并呋喃衍生物的制备方法 (Process for preparing benzofuran derivatives ) 是由 郑保富 高强 李硕梁 杨成武 马振标 于 2019-10-18 设计创作，主要内容包括：本发明公布了一种用于合成苯并呋喃衍生物的制备方法,具体实施方法如下式,本发明合成路线新颖,操作简便,收率高,安全性好,适合工业化生产。其中,还设计了中间体Ⅵ的新型合成方法,进行wittig反应然后关环得到苯并呋喃环。<Image he="202" wi="700" file="DDA0002238714530000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method for synthesizing benzofuran derivatives, which has the following specific implementation method. Wherein, a novel synthesis method of the intermediate VI is also designed, and the benzofuran ring is obtained by carrying out wittig reaction and then closing the ring.)

1. The preparation method of the benzofuran derivative is characterized in that a compound IV and a compound V are dissolved in an organic solvent, subjected to wittig reaction under the action of alkali and then subjected to ring closure to obtain a benzofuran compound,

wherein R is a substituted or unsubstituted aliphatic hydrocarbon group of C1-C8.

2. The method of claim 1, wherein the organic solvent is one or more of tetrahydrofuran, chloroform, toluene, dioxane, DMF, or dichloromethane.

3. The process according to claim 1, wherein the base is potassium tert-butoxide, sodium hydride, n-butyllithium or sodium methoxide.

4. The process of claim 1, wherein the molar ratio of compound V, compound VI and base is 1: 1 (1-2): (1.5 to 3).

5. The method according to claim 1, wherein the reaction temperature is controlled to 0 to 5 ℃.

6. The preparation method according to claim 1, wherein the reaction is carried out by adding THF into compound IV and compound V and protecting with nitrogen. The temperature was reduced to 0 ℃ and a THF solution of potassium tert-butoxide was added to the reaction mixture.

7. The process according to any one of claims 1 to 5, wherein the compound IV is prepared by:

step 1: reacting the compound I with a compound II under the action of methanesulfonic acid to obtain a compound III,

step 2: carrying out esterification reaction on the compound III and thionyl chloride under the action of organic alcohol to obtain a compound IV,

wherein R is a substituted or unsubstituted aliphatic hydrocarbon group of C1-C8,

and step 3: dibromomethane and triphenylphosphine are used to obtain a compound V under the action of an organic solvent,

8. the process according to claim 7, wherein in step 1, compound I is dissolved in methanesulfonic acid and compound II is added in portions.

9. The method of claim 7, wherein the molar ratio of compound I to compound II in step 1 is 1: 1 to 2.

10. The method according to claim 7, wherein the reaction temperature in step 1 is controlled to be within 80 ℃.

Technical Field

The invention relates to the technical field of organic compound synthesis, in particular to a preparation method of a benzofuran compound.

Background

Benzofuran compounds have various good physiological activities, have the effects of resisting tumors, bacteria and oxidation, and are widely concerned. Benzofuran compounds are important skeletons for the synthesis of natural products and medicines. Such as rituximab (lifitegrast), a novel small molecule integration inhibitor, which is used for treating ocular chronic inflammatory diseases, has been approved by the FDA for marketing at 11 days 07/11 in 2016.

The structure of sitagliptin is shown as follows:

the synthesis of 6-carboxylic acid benzofuran (compound VII) as an important intermediate of pharmaceutical compositions is difficult. The synthesis methods disclosed at present mainly include the following methods.

Patent EP 816348 discloses a preparation method, which comprises the steps of cyclizing 4-formyl-3-hydroxybenzoic acid methyl ester serving as a raw material with diethyl bromomalonate, hydrolyzing and acidifying, and then carrying out copper-catalyzed decarboxylation to obtain benzofuran-6-carboxylic acid. The specific synthetic route is as follows:

the method has the disadvantage that the diethyl bromomalonate has irritation and is not beneficial to industrial production.

Patent WO2003070731 discloses a preparation method, which uses m-hydroxybenzoic acid as raw material, after iodination, carries out Sonogoshira coupling reaction, and then cyclizes and hydrolyzes to obtain 6-carboxylic acid benzofuran.

The synthetic method has the defects that Sonogoshira reaction conditions are severe and are not beneficial to industrial production.

Therefore, a new process with high yield, simple operation, short steps and suitability for industrial production is urgently needed to be developed.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The invention aims to provide a preparation method of benzofuran derivatives, in particular to a preparation method of 6-carboxylic acid benzofuran and pharmaceutically acceptable compounds thereof, so as to solve the technical problems of low yield and complex preparation method in the prior art.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

the preparation method of 6-carboxylic acid benzofuran adopts the following synthetic route:

wherein R is a substituted or unsubstituted aliphatic hydrocarbon group of C1-C8.

The reactions in the steps are all conventional reaction types, the reaction conditions are relatively mild, the raw materials are easy to obtain, and higher yield can be obtained.

The 6-carboxylic acid benzofuran compounds are prepared by the above reaction, the reaction time of each step can be monitored by conventional monitoring means, such as TLC (thin layer chromatography) to monitor the reaction degree, and the reaction is continued or finished, and after the reaction is finished, whether the reaction is purified or directly carried out for the next step or the like is selected according to needs.

The conditions for carrying out the above-mentioned reactions in the respective steps can be conventional ones, but the following preferred embodiments can improve the yield of the product, increase the reaction rate, and reduce the cost.

1. And reacting the compound I with a compound II under the action of methanesulfonic acid to obtain a compound III.

Preferably, in step 1, the molar ratio of compound I to compound II is 1: 1 to 2, preferably 1: 1.5.

The reaction temperature in the step 1 is preferably 50-100 ℃, more preferably 70-85 ℃, and even more preferably 80 ℃. The reaction time of the step 1 is preferably 1-5 h, and more preferably 2-3 h.

The following raw material addition sequence and reaction mode can be adopted in the step 1:

and stirring and mixing the compound I and methanesulfonic acid, adding the compound II into the reaction solution, and after the addition is finished, heating to 70-85 ℃ to react for 2-3 hours. Wherein the compound II is added in portions at the temperature of less than 80 ℃.

After the reaction is finished, cooling, adding pure water, and stirring at room temperature. The product was extracted with a mixed solvent of ethyl acetate and methanol, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. And extracting the organic phase by using a 10% NaOH aqueous solution, combining the aqueous phases, and adjusting the pH value of the aqueous phase to 3-4 by using concentrated hydrochloric acid. Filtering, and vacuum-pumping to obtain the compound III.

2. And carrying out esterification reaction on the compound III and thionyl chloride under the action of organic alcohol to obtain a compound IV.

Wherein R is a substituted or unsubstituted aliphatic hydrocarbon group of C1-C8.

Preferably, in step 2, R is selected from C1-C8 substituted or unsubstituted aliphatic hydrocarbon groups, preferably methyl, ethyl, isopropyl, tert-butyl, and more preferably methyl.

Preferably, in step 2, the organic alcohol is selected from methanol, ethanol, isopropanol, and tert-butanol, preferably methanol and ethanol, and more preferably methanol.

Preferably, in the step 2, the molar ratio of the compound III to the thionyl chloride is 1: 1 (1-2), and preferably 1: 2.

The reaction temperature in the step 2 is preferably 50 to 100 ℃, and more preferably 60 ℃. The reaction time of the step 2 is preferably 1-5 h, and more preferably 2-3 h.

3. Dibromomethane and triphenylphosphine are used for obtaining a compound V under the action of an organic solvent.

Preferably, in step 3, the organic solvent is selected from one or more of toluene, dioxane, N-dimethylformamide or dimethylsulfoxide, and is preferably toluene.

Preferably, in the step 3, the molar ratio of the dibromomethane to the triphenylphosphine is 1: 2 (2-3), and preferably 1: 2.2.

The reaction temperature in the step 3 is preferably 80-130 ℃, more preferably 100-120 ℃, and further preferably 120 ℃. The reaction time of the step 3 is preferably 20-30 h, and more preferably 24 h.

The following raw material adding sequence and reaction mode can be adopted in the step 3:

dissolving dibromomethane and triphenylphosphine in toluene, and reacting for 20-30 h at 100-120 ℃.

And after the reaction is finished, cooling, filtering, washing a filter cake with petroleum ether, collecting the filter cake, and performing spin drying to obtain a compound V.

4. And (3) carrying out wittig reaction on the compound IV and the compound V under the action of alkali and an organic solvent, and then closing a ring to obtain the benzofuran compound VI.

Preferably, in step 4, the base is selected from potassium tert-butoxide, sodium hydrogen, n-butyllithium, sodium methoxide, preferably potassium tert-butoxide.

Preferably, in step 4, the organic solvent is one or more selected from tetrahydrofuran, chloroform, toluene, dioxane, DMF or dichloromethane, and is preferably tetrahydrofuran.

Preferably, in step 4, the molar ratio of compound V to compound VI is 1: 1 to 2, preferably 1: 1.5. The molar ratio of compound V to base is 1: 1.5 to 3, preferably 1: 2.2.

The reaction temperature in the step 4 is preferably-78 to 35 ℃, preferably 0 to 10 ℃, and more preferably 5 ℃. The reaction time of the step 4 is preferably 1-3 h, and more preferably 2-3 h.

The following raw material addition sequence and reaction mode can be adopted in the step 4:

and adding THF (tetrahydrofuran) into the compound IV and the compound V, and protecting with nitrogen. And cooling to 0 ℃, adding a THF solution (1M) of potassium tert-butoxide into the reaction solution, stirring for 30min, continuously adding the THF solution (1M) of potassium tert-butoxide, and reacting for 1 hour at 0-10 ℃. The preferred addition mode of the potassium tert-butoxide is dropwise addition, and the preferable addition temperature is 0-10 ℃.

After the reaction is finished, adding petroleum ether, filtering, concentrating to obtain oily liquid, pulping with petroleum ether, filtering, concentrating the filtrate to obtain a crude product of the compound VI, and directly using the crude product in the next reaction.

Compared with the prior art, the invention has the beneficial effects that:

1) the invention aims to provide a synthesis method of benzofuran compounds, which has the advantages of simple operation, short reaction route, cheap raw materials, low cost, safety, environmental protection and suitability for industrial production.

2) Compared with the prior art, the invention discloses a compound VII synthesized by closing the ring through wittig reaction, which has simple operation and mild reaction condition and avoids low-temperature reaction.

3) The compound VI can be subjected to one-step hydrolysis reaction to obtain a sitaxel important intermediate, namely 6-carboxylic acid benzofuran.

The method provides a new synthesis method of benzofuran compounds, simplifies reaction steps, has low cost, is safe and environment-friendly, and is suitable for industrial production.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that the specific examples are intended only to further illustrate the invention and are not intended to limit the scope of the invention. In the following examples, experimental conditions not shown were carried out according to a conventional method.